Plasma gas discharge treatment for improving the compatibility of biomaterials

ABSTRACT

A method of treating articles to improve their biocompatibility is disclosed. A polymeric substrate material is positioned within a reactor vessel and exposed to plasma gas discharge in the presence of an atmosphere of an inert gas and then in the presence of an organic gas, such as a fluorinated hydrocarbon gas, which forms a thin, biocompatible surface covalently bonded to the surface of the substrate. The method is particularly useful in the treatment of vascular graft materials to produce grafts that are both thrombi- and emboli-resistant.

This invention was made with government support under Grant No. HL22163by the National Heart, Lung and Blood Institute, National Institute ofHealth.

This application is a continuation of U.S. Ser. No. 06,803,100, filedNov. 27, 1985, now abandoned, which is a continuation-in-part of U.S.Ser. No. 06/709,990, filed Mar. 11, 1985, issued as U.S. Pat. No.4,656,083, which is a continuation of U.S. Ser. No. 06/519,383, filedAug. 1, 1983, now abandoned.

TECHNICAL FIELD

This invention relates to a method of improving the biocompatibility ofbiomedical articles and to such articles for use as dental andorthopedic implants, and blood contacting devices for diagnosis or fortherapy, including vascular prostheses, heart valves, etc.

BACKGROUND ART

Biomedical articles, particularly those which are in contact with blood,require certain properties to ensure acceptance by the body and bodytissue for incorporation into the body on a long-term basis.

Prosthetic arterial replacements in humans to correct impaired arterialflow are well accepted. Grafts of polyester, tetrafluoroethylene andother synthetic materials are commonly used where the diameter of thearterial replacement is generally greater or equal to six millimeters;however, synthetic vascular prostheses with diameters less than sixmillimeters have not been conventionally employed, generally because ofthe increased probability of the development of obstructions due tothrombosis and/or vessel wall thickening.

The search for an ideal prosthetic arterial graft began some 25 yearsago, with research and development focusing on smooth-walled,non-thrombogenic "inert" implants. Ideas centered around Teflon andDacron low-porosity weaves which did not require preclotting, as therewas no blood leakage at surgery. Over the past 10 years, more "reactive"or initially thrombogenic grafts have increasingly been used in surgicalapplications. Knits, external and finally internal velours appeared, allof which were porous, increasingly textured surfaces requiringpreclotting. These seemed to be better incorporated into the body on along-term basis, both in terms of external tissue fixation by fibroblastingrowth through the pores and possibly also through the luminalanchoring of a non-thrombogenic, biologically passivated surface.

The real challenge for vascular substitutes today is the smallerdiameter (<4 mm) and/or low blood flow situation as is encountered inthe femoral-popliteal region, or more importantly, in the coronaryarteries. While patency rates run as high as 99% at 5 years in aorticgrafts, femoral-popliteal grafts exhibit 50-70% patency at 5 years atbest. Coronary artery replacement by prosthetic materials has barelybeen attempted.

Porous polytetrafluoroethylene tubing for use in vascular grafts isdescribed in U.S. Pat. Nos. 3,962,153 and 3,953,566. U.S. Pat. No.4,304,010 describes the application of a porous elastomeric coating overthe outside surface of stretched porous polytetrafluoroethylene tubingfor use in vascular grafts. U.S. Pat. No. 4,321,211 describesincorporating an anticoagulant substance in a stretched porouspolytetrafluoroethylene material and incorporating an outer porouselastomeric coating around the PTFE material containing a substancewhich counteracts the anticoagulant substance. U.S. Pat. No. 4,208,745describes a stretched PTFE polymer in which the fibrous structure on theinside surface is made up of finer fibers than the fibrous structure onthe outside surface face. U.S. Pat. No. 4,193,138 describes thepreparation and use of stretched porous PTFE materials in which thepores are filled with a water-insolubilized, water-soluble polymer, suchas polyvinyl alcohol. U.S. Pat. No. 4,312,920 describes surfacemodification of polyurethane with an alloy of silicone rubber, thematerial being useful in the fabrication of biomedical articles. U.S.Pat. No. 4,254,180 describes the preparation of a heparin-receptivesurface on a mixture of a particulate resin and a graphite. U.S. Pat.No. 4,265,927 discloses heparinizing a charged surface of a biomedicalarticle with a fine-grained, colloidal aqueous solution of a complexcompount of heparin and a cationic surfactant. U.S. Pat. No. 4,116,898describes coating a polymeric substrate with a particular compoundincorporating a heparin-like substance. U.S. Pat. No. 4,179,751discloses the use of poly(alpha-olefin-sulfone) membrane prepared fromC₈ -C₁₈ alpha-olefins and sulfur dioxide for use in biomedical articles.U.S. Pat. No. 4,042,978 describes preparation of a plastic forprosthetics made up of repeating units having the structure --CH₂ --CH₂--O--. U.S. Pat. No. 3,853,062 describes use of a knitted linearpolyester fabric which has been treated with a compacting solution foruse as a vascular graft. U.S. Pat. No. 3,839,743 describes preparationof a thrombo-resistant article made by coating a surface in contact withblood with an organic polymeric material having fluoroalkyl side chainsof the formula C_(n) F_(2n+1) C_(m) C_(2m) --. U.S. Pat. No. 4,167,045describes the use of a woven Dacron material which has its surfacemodified to make it thrombo-resistant. U.S. Pat. No. 4,178,329 describesa graft copolymer of a particular type for use in fabrication ofbiomedical materials for biomedical uses. U.S. Pat. No. 4,047,252describes a double-velour, synthetic vascular graft made of Dacron. U.S.Pat. No. 3,940,802 describes a blood bag fabricated from plasticizedpolyvinyl chloride and a thermoplastic polyester-based polyurethane.U.S. Pat. No. 4,319,363 describes a tube of collagenous tissue subjectedto glutaraldehyde tanning to give cross-linked collagen fibrils for useas vascular graft material.

A review of the safety and performance of currently available vascularprostheses can be found in Vol. 4, No. 4, American Society forArtificial Internal Organs, J. D. Mortensen, "Safety and Performance ofCurrently Available Vascular Prostheses." This article also references acomprehensive literature search performed for the Federal Food and DrugAdministration by the Utah Biomedical Testing Laboratory on vasculargrafts and their safety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of the apparatus used in treatingarticles.

FIGS. 2 and 2A are graphic evaluations of treated and untreatedprosthetic arterial grafts using the ESCA (electron spectroscopy forchemical analysis) technique.

FIGS. 3 and 3A compare ESCA spectra for treated Dacron and untreatedTeflon.

FIG. 4 is a graph of patency versus time of a 4.5 mm ID, high-porosityDacron velour knit treated in accordance with this invention and acomparative untreated high-porosity Dacron velour knit in an ex vivobaboon femoral shunt research model.

FIG. 5 is a graph of mean relative blood flow versus time of the sametreated and untreated velour knits as in FIG. 4, again for the samebaboon femoral shunt research model.

FIG. 6 is a graph of patency versus time of 5 mm ID Dacron weaves, onetreated in accordance with the invention, a second untreated, and athird treated only with argon in an ex vivo baboon femoral shuntresearch model.

FIG. 7 is a graph of mean relative blood flow versus time of the same 5mm ID Dacron weaves as in FIG. 6, again for the same baboon femoralshunt research model.

FIG. 8 presents the rate of change of total emboli volume as a functionof time for TFE treated and untreated Dacron weaves.

FIG. 9 reports data similar to FIG. 8 for Dacron knits.

FIG. 10 reports data similar to FIG. 8 for TFE treated and untreatedGoretex®.

FIG. 11 shows patency as a function of time for preclotted grafts.

FIG. 12 reports mean relative blood flow as a function of time for thepreclotted grafts of FIG. 11.

DISCLOSURE OF INVENTION

It is an object of this invention to provide a method of treatingsubstrate materials to improve their biocompatibility by exposure of thesubstrate material to plasma gas discharge in the presence of at leastone gas capable of forming a biocompatible surface on the substrateexposed to the plasma gas discharge.

It is a further object of this invention to provide surface-modifiedbiomedical articles and a method of making such articles which arethrombo-resistant and/or blood biocompatible over substantial periods oftime.

It is a further object of this invention to provide articles whosesurface is treated in a plasma gas discharge in the presence of one ormore selected gases to improve the biocompatibility of the surface ofthe articles being treated.

It is a further object of this invention to provide vascular grafts anda method of making such by exposure of a vascular graft material toplasma gas discharge in the presence of at least one gas capable ofrendering the surface of the graft in contact with blood or body tissuesubstantially thrombo-resistant and subject to reduced embolization oversubstantial periods of time.

It is a further object of this invention to provide vascular graftswhose interior surface exposed to blood is exposed to plasma gasdischarge in the presence of one or more selected gases to render thesurface in contact with the blood substantially thrombo- andemboli-resistant over substantial periods of time without affecting theproperties of the graft material, such as porosity, texture, area ofsurface contact, and mechanical properties.

These and other objects are accomplished by providing a substratematerial and exposing the surface of the substrate material to plasmagas discharge in the presence of at least one gas capable of forming abiocompatible surface on the substrate in the form of a homogeneous,covalently bound, mechanically strong, ultra-thin layer.

BEST MODE FOR CARRYING OUT THE INVENTION

There is a need for biocompatible materials suitable for implants, bloodcontacting devices for diagnosis or therapy, vascular prostheses, andother such articles which can be used over substantial periods of time,particularly when in contact with blood, which are substantiallynon-thrombogenic. There is also a need for vascular graft material whichcan be used as femoral-popliteal or popliteal-tibial arterialreplacements and possibly in heart bypass operations where the necessarysmall diameter of the replacement causes difficulties with presentlyused prostheses because of their frequent tendency to block off rapidlywith blood thrombus.

Providing organic surface coatings on substrate materials by means ofplasma polymerization is known. An article by H. Yasuda, J. Macromol.Sci.-Chem., A10(3), pp. 383-420 (1976), entitled "Plasma forModification of Polymers," describes the effect of non-polymer-formingplasma on substrate materials and the effects of polymer-forming plasmaon plasma-susceptible polymer substrates.

"Plasma," as used herein, is used in the sense of "low-temperatureplasma" or "cold plasma" produced by glow discharges. Plasmas created byelectric glow discharges contain a variety of species which arechemically active or energetic enough to cause chemical reactions, i.e.,covalent bonding to a suitable substrate material. For example,electrons, ions of both charges, excited molecules at various levels ofexcitation, free radicals, and photons of various energies are createdby cold plasma.

What is described herein is the deposition of certain gases asbiocompatible polymers on clean surfaces of substrate materials for useas tissue implants or other orthopedic implants, blood-contactingdevices for diagnosis and/or therapy, catheters, vascular graftmaterials, such as porous, knitted or woven Dacron materials, materialswith a polytetrafluoroethylene deposition, such as Goretex® or otherbiomedically suitable materials. By "deposition" is meant the formationof a covalent bond between the substrate and the coating deposited onthe substrate surface.

The coatings are typically thin, perhaps only a monomolecular layer, andin some cases are highly cross-linked. Polymer films generated in thismanner have been shown to be ultra-thin, tightly bound, andpinhole-free.

The substrate materials from which the biomedical articles of thisinvention may be made include a wide range of materials. Generally,synthetic resins are conventionally employed to fabricate articles. Suchsubstrate materials are frequently fabricated from polyethylene,polyacrylics, polypropylene, polyvinyl chloride, polyamides,polystyrene, polyfluorocarbons, polyesters, silicone rubber, hydrocarbonrubbers, polycarbonates and other such synthetic resin materials. Thesubstrate may be rigid or flexible, woven or nonwoven, molded or shaped,porous or nonporous. The substrate is first formed into a desired shapeor configuration, depending on the use to which it is to be put, suchas, for example, a valve, pin, catheter, sleeve, vascular graft,surgical tubing, etc. The surfaces of the substrate to be treated arethen subjected to plasma gas discharge in the presence of at least onegas to form a homogeneous, tightly bound, mechanically strong,ultra-thin polymeric layer on the surface of the substrate.

Preferably, plasma gas polymerization is carried out by positioning thesubstrate in a vacuum chamber, connecting the vacuum chamber to a sourceof gas, and applying a high radio frequency energy to the substrate inthe vacuum chamber by means of a suitable generator. When subjected tothe glow discharge energy, the gas molecules present in the vapor arebombarded by electrons having high enough energy to rupturecarbon-hydrogen bonds (about 4 eV), leading to the formation of freeradicals and other chemical species.

From this point, polymerization is initiated, and a thin, uniformpolymer film is deposited upon the substrate located within the vacuumchamber. Organic gases in the vapor state, like other gases, are ionizedby bombardment with electrons under the discharge conditions, and suchions, when neutralized, have excess energy that leads to rapidpolymerization. Solid films can be prepared from organic gases at ratesof several ounces per KWH. The thickness can be controlled to within ±10Å and is dependent on the concentration of the gas and the time to whichthe substrate is exposed to the plasma gas discharge.

Subjecting the substrate to glow discharge energy also affects thesurface of the organic polymer substrate in contact with thelow-temperature plasma gas. Energetic species from the organic polymersubstrate surface break organic bonds with possible evolution of gaseousproducts, such as hydrogen, and formation of carbon-free radicals. Theseradicals lead to chemical reactions at the surface of the substrate andmay result in surface cross-linking and modification of the surfaceproperties of the substrate. The free radical sites formed on thesubstrate may also be employed directly to initiate polymerization witha new polymer bond firmly to the substrate by carbon-carbon linkages.

Gases which may be used for forming a coating or film onto substratematerials include those capable of forming a biocompatible coatingbonded to the substrate material in the presence of plasma gasdischarge, such as gaseous hydrocarbons, halohydrocarbons, halocarbonsand silanes. Specifically, tetrafluoroethylene, ethylene andchlorofluoroethylene may be used.

The parameters which define the system for plasma gas discharge includethe gas itself, the flow rate of the gas, the initial system pressure,the geometrical design of the reactor, and the radio frequency ordischarge power of the glow-discharge unit. The inductance orcapacitance method of plasma discharge may be utilized, or othersuitable method. Electrical energy is imparted to a neutral species, inthis case, the gas, to convert it to an active species. The plasmadischarge also creates active species in the surface of the substratematerial when an organic polymer resin substance is used. The activegaseous species is covalently bonded to the substrate.

In the treatment of vascular graft materials to render them morebiocompatible, particularly more blood compatible, it is preferable toinitially clean the vascular graft material prior to exposure to plasmagas discharge with suitable solvents, followed by drying under vacuum.The graft material is then preferably subjected to plasma gas dischargeat 5-100 watts energy in the presence of an atmosphere of insert gas,such as argon, for surface etching and activation of the substrate. Thisis followed by plasma gas discharge treatment at 5-100 watts energy inthe presence of an atmosphere of the gas to be deposited as abiocompatible coating bonded to the substrate material. The pressuresutilized may vary but are generally within 0.10 to 10 torr. Thetreatment time the substrate is subjected to glow discharge may rangefrom 5 minutes to 1 hour. The surface coating obtained is uniform overthe entire surface of the substrate, is non-leachable, and isrepeatable.

The following examples are illustrative of the method and articlesclaimed, but are not considered to be limiting.

FIG. 1 illustrates schematically the apparatus used for treatingvascular graft materials. The vascular graft materials 1 were suspendedwithin a glass reactor 2 in such a way that the gas used to modify thesurface flowed into the reactor vessel at 3 and through the interior ofthe graft materials 1. The reactor vessel was surrounded by a series ofinduction coils connected to a glow discharge generator. A gas outlet 5in the reactor vessel was connected by flexible stainless steel tubingto an outflow solenoid valve 6, which, in turn, was connected to aliquid nitrogen trap 7, backstreaming filter 8, and vacuum pump 9.Gas-containing vessels 10, used to modify the surface of the vasculargraft materials within the reactor vessel, were connected to the reactorvessel by gas-distributing pipes 11, with gas flow controlled by aninflow solenoid valve 12 and micrometer flow valve 13. A pressure sensor14, connected to sense gas pressure within the reactor vessel, wasconnected to a pressure meter 15.

Small diameter, vascular graft materials (4.5 and 5 mm ID) composed ofwoven or knitted Dacron velour (polyethylene terephthalate) weresubjected to cleaning by 20-minute exposure in trichloroethylene toultrasound in an ultrasonic cleaning apparatus, followed by a similarprocedure in methanol and deionized water. The specific graft materialsused included 4.5 mm ID Sauvage filamentous external velour graftshaving mean porosities of 1420, 1917 and 2867 cc/cm² -min, and 5 mm IDUSCI DeBakey weave grafts with a porosity of 178 cc/cm² -min.

The cleaned grafts were mounted in the reactor vessel, supported alongthe central longitudinal axis of a cylindrically designed glow dischargeglass reactor, as previously described, and dried under vacuum to <0.01torr. The reactor was flushed with argon gas for 5 minutes at 0.5 torr.With the argon pressure adjusted to 0.20 torr, the samples were reactedfor 5 minutes in glow discharge at about 15 watts. The glow dischargewas discontinued and argon allowed to continue flowing through thesample at 0.20 torr for 5 minutes. The plasma gas discharge resulted insurface etching and activation of the Dacron vascular graft materials bythe argon. The argon gas was then displaced from the reactor vessel bytetrafluoroethylene (TFE) gas. The samples were equilibrated in thetetrafluoroethylene atmosphere at 0.50 torr for 5 minutes and thensubjected to a 30-minute glow discharge treatment at 0.20 torrtetrafluoroethylene and 15 watts energy. After the glow dischargetreatment, the graft materials were maintained in the reactor vesselunder the atmosphere of tetrafluoroethylene gas for about 4 hours. Theresultant treated grafts had an interior surface which was highlyfluorinated in a homogeneous, reproducible manner, as demonstrated bysubsequent ESCA (electron spectroscopy chemical analysis) studies.

FIGS. 2 and 3 illustrate ESCA spectra of glow discharge treated graftmaterials treated by the method previously described compared to theuntreated graft materials.

Using ESCA data, C/F ratios in treated fabric samples were determined.Such measurements permit establishment of reproducible and uniform glowdischarge treatments and results, as suggested by Table I.

                  TABLE I                                                         ______________________________________                                        VARIATION OF SURFACE COMPOSITION                                              WITH TIME EXPOSED TO TFE GLOW DISCHARGE                                       (Medium Porosity Dacron Knit - 15 watts, 0.2 torr)                            EXPOSURE TIME     C/F                                                         ______________________________________                                         1                0.98                                                         5                0.92                                                        20                0.86                                                        30                0.72                                                        40                0.72                                                        PTFE (THEORY)     0.50                                                        ______________________________________                                    

Measurements along graft length and across the graft wall verifieduniformity of C/F ratios ranges at 0.67-0.71.

The properties of the substrate material remained otherwise unchanged.The surface texture of the treated materials, as demonstrated byscanning microscopy, and the mechanical behavior of the vascular graftmaterials were not altered. For example, graft porosity remainssubstantially unchanged, as reported in Table II.

                  TABLE II                                                        ______________________________________                                        THE EFFECT OF TFE GLOW DISCHARGE                                              TREATMENT ON DACRON GRAFT POROSITY                                            (Units = CC of water/cm.sub.2 -min × 10.sup.-2)                                       UNTREATED                                                       DACRON GRAFT  CONTROL     TFE TREATED                                         ______________________________________                                        Woven          1.8 ± 0.2                                                                              1.8 ± 0.1                                       Medium Porosity                                                                             19.2 ± 1.0                                                                             20.9 ± 2.1                                       Knit                                                                          High Porosity 28.7 ± 2.1                                                                             28.5 ± 1.3 - Knit                                ______________________________________                                    

Similar vascular graft materials of Dacron were also treated solely byplasma gas discharge in an argon atmosphere at 0.20 torr for 10 minutesat 50 watts energy to modify the surface by activation and etching andsubsequent oxidation of the etched material surface by exposure to theatmosphere.

The glow discharge treated and control untreated grafts were placed inan ex vivo arterial-venous shunt connecting the cannulized femoralartery to the cannulized femoral vein of a baboon by means of a Silasticshunt. This ex vivo model possesses platelet, fibrinolytic andthrombogenic functions similar to humans, and thus is clinicallyrelevant to man. In general, test results were strongly dependent onmaterial surface properties, with increasingly thrombogenic materialsshowing higher platelet reactivity and a more rapid thrombus buildup.The graft materials were evaluated by measuring patency, flow rate,platelet consumption, platelet survival, and graft platelet depositionduring three time periods after graft placement:

(1) acute response (1-2 hours)

(2) steady state response (>1 day)

(3) passivated response (>/week)

The graphs (FIGS. 4-7) illustrate the average of several experiments ofpatency and mean relative blood flow versus time of vascular grafts(tetrafluoroethylene treated, untreated, and argon-only treated) in anex vivo baboon female shunt research model. Significantly improvedpatency and correspondingly improved flow were observed intetrafluoroethylene treated vascular grafts as compared with theuntreated control Dacron grafts and the argon-etched only vasculargrafts. The argon-etched only vascular grafts exhibited poorer patencyand flow when compared with the untreated control Dacron vasculargrafts.

In particular, referring to FIG. 4, the 4.5 mm ID vascular graftstreated in accordance with the invention, after one week, exhibited animproved patency when compared to the untreated vascular grafts. In FIG.6, the 5 mm ID treated vascular grafts, after one week, exhibited animproved patency when compared to the untreated vascular grafts.

By means of a laser light scattering microemboli detection technique, itwas determined that the untreated vascular grafts generatedapproximately three times more emboli than the tetrafluoroethylenetreated vascular grafts. Table III reports results of tests using freshwhole baboon blood. The data demonstrates that the improved ex vivopatency of the TFE treated graft substrate materials is not due toincreased embolization.

                  TABLE III                                                       ______________________________________                                        RELATIVE IN VITRO EMBOLIZATION                                                OF SILASTIC TUBING AND TFE TREATED                                            AND UNTREATED VASCULAR GRAFT MATERIALS                                        (Units = (platelets/day-cm.sup.2) × 10.sup.8 ; Size range - 80-800      u)                                                                                   GORE-   DACRON    DACRON    SILASTIC                                          TEX ®                                                                             KNIT      WEAVE     TUBING                                     ______________________________________                                        Untreated                                                                              8.56 ± 4.39                                                                          8.68 ± 0.34                                                                          8.32 ± 1.28                                                                        1.0 ± .27                             Control                                                                       TFE Treat-                                                                             1.55 ± 0.32                                                                          2.69 ± 0.78                                                                          3.72 ± 0.89                                                                        --                                       ment                                                                          ______________________________________                                    

FIGS. 8-10 report total emboli volume observed over time for the Dacronknits and weaves and for Goretex® grafts. In each example, the TFEplasma treated sample is compared with the untreated graft. All TFEplasma treated grafts showed a marked decrease in embolization rate overuntreated materials. The improvement was noted even for Goretex®,indicating that the TFE glow discharge treatment results in a differentand more blood-compatible fluoropolymer surface than for untreatedpolytetrafluoroethylene polymers.

Treated and untreated graft segments were also prepared to investigatethe ability of a pre-clot technique to maintain hemodynamic competence.Graft segments were pre-clot following a Fogarty catheter methoddescribed below. After preclotting, grafts were connected to thearterial side of the ex vivo baboon femoral shunt model and the residualclots were washed out. The shunt-vascular graft segment was then exposedto arterial blood at physiologic pressures. No blood leakage wasobserved from any graft material which was pre-clot with this process.

TFE treated and untreated medium-porosity Dacron velour knit grafts(2000 cc/cm² -min) were tested for patency and blood flow after thegrafts were preclotted using the baboon model. Vascular grafts supportedby heat-shrink Teflon tubing and filled with sterile Ringer's citrateddextrose solution (RCD) were attached to the arterial side of the shunt.A Fogarty catheter with the balloon deflated was placed through thegraft segment until it became visible in the shunt. The arterial clampwas then released for several seconds, allowing 20-30 cc of blood toflow through the graft into a collecting pan.

The shunt-vascular graft segment was then opened to the babooncirculatory system, permitting the graft material to become completelywetted by the baboon arterial blood. After 5 minutes, the shunt-vasculargraft segment was removed from the arterial connector of the baboonshunt. With the Fogarty remaining in place, the blood within the graftwas allowed to drain out. The upstream and downstream portions of theshunt itself were then reconnected and blood flow as reestablished andmeasured.

When the blood in the collecting pan had completely clotted (usually20-30 minutes), the Fogarty balloon was fully inflated and slowly passedonce completely through the now pre-clot graft. This removed theremaining gross clots and likely generated a more uniform flow surface.The baboon shunt was again clamped and opened, and the graft wasreconnected to the arterial side of the shunt system. The shunt-vasculargraft segment was filled again with blood and then re-clamped downstreamof the graft. The clamp was released, and 10-20 cc of whole blood wasallowed to flow through the graft to a collecting pan to wash out anyresidual clot.

The graft was connected to the venous side of the shunt and all clampswere released, permitting blood flow through the shunt-vascular graftsystem. This indicated the start, t=0, of an experiment. Whole blood forplatelet counts and blood flow were sampled before starting the pre-clotprocess and at t=0 for comparison. These values did not changeappreciable during the pre-clot process.

FIGS. 11 and 12 report percent patency and mean relative blood flow as afunction of time after placement. The data demonstrate that the plasmaTFE treated substrates perform better than untreated grafts, even afterpreclotting.

We claim:
 1. A method of making a vascular prosthesis from a woven orknit polymeric substrate material whose surface exposed to blood istreated to render the vascular prosthesis both thrombi- andemboli-resistant, comprising:exposing the surface of the woven or knitsubstrate material to be exposed to blood to a radio frequency plasmagas discharge in the presence of a fluorinated hydrocarbon gas, whereinthe fluorinated hydrocarbon gas forms a thin coating on the surfaceexposed to blood of the woven or knit polymeric substrate, said thincoating characterized as highly cross-linked, covalently bound to thewoven or knit polymeric substrate material, and not changing themechanical behavior of the woven or knit polymeric substrate material orits surface texture.
 2. The method of claim 1 wherein the fluorinatedhydrocarbon gas is present at a pressure of from 0.1 to 1.0 torr, andwherein the radio frequency plasma discharge energy is from 5 to 100watts.
 3. The method of claim 1 wherein the fluorinated hydrocarbon gasis tetrafluoroethylene.
 4. The method of claim 1 wherein the wovenpolymeric substrate material is a woven or knit polyethyleneterephthalate.
 5. A surface modified vascular graft material whosetreated surface, when exposed to blood, is both thrombi- andemboli-resistant over extended periods of time, comprising:a woven orknit polyethylene terephthalate substrate material having a thin,covalently bonded coating on the treated surface, wherein the coatingconsists essentially of a highly cross-linked fluorocarbon polymerresulting from a radio frequency plasma discharge polymerization processconducted in a fluorinated hydrocarbon gaseous atmosphere, and whereinthe coating does not change the mechanical behavior of the woven or knitpolyethylene terephthalate substrate material or its surface texture. 6.The surface modified vascular graft material of claim 5 wherein thefluorinated hydrocarbon gaseous atmosphere consists oftetrafluoroethylene.
 7. The surface modified vascular graft material ofclaim 5 wherein the fluorinated hydrocarbon gaseous atmosphere has apressure in the reactor vessel from 0.1 to 1.0 torr, and wherein theelectric glow discharge polymerization process uses a frequency energyrange of from 5 to 50 watts.
 8. A method for making a surface modifiedwoven or knit substrate material characterized by having a coatedsurface, when exposed to blood, is both thrombi- and emboli-resistantover extended periods of time, comprising:exposing a surface of thewoven or knit substrate material to a plasma gas discharge in thepresence of an inert gas to etch and activate the surface of the wovensubstrate; and exposing the etched and activated surface of the woven orknit substrate to a plasma gas discharge in the presence of afluorinated hydrocarbon gas, wherein the surface becomes coated by athin, covalently bound fluorocarbon polymer, characterized by beinghighly cross-linked and by not changing the mechanical behavior of thewoven or knit substrate material or its surface texture.
 9. The methodof claim 8 wherein the inert gas is argon and the fluorinatedhydrocarbon gas is tetrafluoroethylene.
 10. The method of claim 8wherein the woven or knit substrate is a fabric of polyethyleneterephthalate.